Cell-cell adhesion plays a critical role in tissue and organ assembly during embryogenesis, tissue remodeling during development and wound repair, and tissue maintenance in the adult. Disruption of normal cell adhesion is a critical step in tumor metastasis, and also plays a role in inherited and autoimmune blistering diseases. An understanding of the mechanisms by which cell adhesion is established, maintained and regulated will thus provide fundamental insights into normal cell and developmental processes, and will also help us understand how these processes go awry in disease. Much of the basic cell adhesion machinery was present in the common ancestor of all animals, and thus we can make use of insights from different model organisms to help drive forward progress in our field. We developed a model system to study the coupling of cell adhesion and signal transduction, using the fruit fly Drosophila. The tools available in this system allow us to combine very powerful genetic approaches with the ability to study cell biological events in the context of the intact animal, often in real time. Results of these analyses can then be applied to human cells, and the results of parallel studies in mammalian cells and other systems incorporated into our own work in Drosophila. This synergy drives much more rapid progress than could be achieved in any one system. Work in many labs in the past ten years have provided us with a static model for the cell-cell adhesion machinery, revealing in outline how the core complex of cadherins and catenins at adherens junctions (AJs) mediates adhesion and link adhesive junctions to the actin cytoskeleton. Our current challenge is to extend this work and determine how adhesion is regulated to allow the diverse tissue architectures and cell behaviors found in the developing embryo. Here we focus on three unanswered questions in this area, each providing the basis for one of our Specific Aims, which are as follows; Aim 1: Define the function of additional AJ proteins. Aim 2: Define the mechanisms by which AJs are coupled to the actin cytoskeleton. Aim 3: Characterize novel roles of AJ proteins in cell polarity, spindle orientation and MT organization